Ultrasonography in the diagnosis of hemorrhagic cystitis - a complication of bone marrow transplantation in pediatric oncology patients.

OBJECTIVE: The aim of this study was to evaluate the usefulness of ultrasonography in the diagnosis of hemorrhagic cystitis following bone marrow transplantation in children.
MATERIAL AND METHODS: The study involved an analysis of clinical material and the results of imaging tests performed in 334 patients who underwent hematopoietic cell transplantation. Ultrasonographic findings in 42 patients with hemorrhagic cystitis were analyzed in detail. The ultrasound images served to assess the severity of hemorrhagic cystitis and the results were compared with the clinical assessment of the disease on the Droller scale, as well as the laboratory and endoscopic tests.
RESULTS: In the studied group of patients hemorrhagic cystitis following allogeneic transplantation was diagnosed in 12.5% cases. 73.8% patients received transplants from unrelated donors, 26.2% - from compatible siblings. The study revealed a higher incidence of hemorrhagic cystitis in children above 10 years of age. Grade 3 according to the Droller was diagnosed in 42.9%, grade 2 - in 30.9%, grade 4 - in 14.3%, and grade 1 - in 11.9% patients. The number of ultrasound examinations depended on the clinical symptoms, severity, duration and co-occurrence of other complications following the transplantation and was within the 1-15 range (average: 4.6). Grades 3 and 4 were related to the poor clinical condition of the patients and to their longer hospitalization. During this period there was an increased risk of renal malfunction and acute renal failure, post-inflammatory narrowing of the ureters, hydronephrosis, and in grade 4 the fibrosis of the bladder with reduced bladder capacity. Analyses demonstrated a significant correlation between the ultrasound image of the bladder wall and the clinical severity.
CONCLUSIONS: Ultrasound with Doppler options remains the primary diagnostic tool in the evaluation of hemorrhagic cystitis, and is useful in terms of its diagnosis, determination of the severity, and monitoring of the treatment.

Introduction

Hemorrhagic cystitis is a fairly common complication of bone marrow transplants in pediatric cancer patients(. By definition, it is characterized by severe hematuria of varying intensity with accompanying symptoms of the urinary tract dysfunction manifested as bladder and urethra pain, polyuria, dysuria and the occurrence of urgency episodes(. Less often it takes the form of asymptomatic hematuria(.

The incidence of hemorrhagic cystitis varies(. In children, it occurs mainly after allogeneic transplants (allotransplants) in which blood stem cells are derived from a related or unrelated donor, compatible or partly compatible in terms of the human histocompatibility system – HLA(. Its incidence is less common after autogeneic transplants (autotransplants) in which progenitor cells are derived from the recipient (the patient himself is the donor)(. After allotransplants haemorrhagic cystitis occurs in 6–26.9% patients and after autotransplants – in 0.85–9%(.

Depending on the time of its occurrence, hemorrhagic cystitis is classified as early-onset and late-onset(. The early onset is detected when the disease manifests itself during preparations for the transplantation, or within 72 hours after the completion of preconditioning. After that time, it is diagnosed as late-onset(.

The early onset is caused by damage done to the urothelium by toxic drug metabolites, the late onset is caused by viruses which act on the urothelium that is damaged due to conditioning(. The late onset is characterized by greater severity and leads to intricate complications(.

The disease process usually lasts from several to over a dozen days, and tends to be self-limited. It is extremely rare for the applied treatment not to produce the desired results and for the inflammation to continue up to several months(. In order to diagnose hemorrhagic cystitis, one must exclude urinary tract infections (bacterial and fungal) and coagulation disorders(. The primary diagnosis of hemorrhagic cystitis includes ultrasound screening (B-mode, Doppler tissue flow techniques, 3D/4D volume) and laboratory testing. Apart from traditional urine analysis, the applied procedures also include qualitative and quantitative methods of polymerase chain reaction (PCR) in order to identify and assess the amount of viral load in the urine sample and the plasma(.

In their clinical evaluation of changes in the bladder and functional disorders resulting from them, various centers follow different severity scales of hemorrhagic cystitis(. The most widely accepted grading system is the Droller scale, in which the author distinguishes four degrees of hemorrhagic cystitis severity(. Table 1 shows the grades of the inflammatory process according to the Droller scale.

Tab. 1

Diagnoses in the group of pediatric patients with allotransplants

Diagnosis	Number of patients	Percentage of patients
Aplastic anemia	24	9,3%
Acute lymphoblastic leukemia	84	32,7%
Acute myeloblastic leukemia	56	21,8%
Lymphomas	11	4,3%
Metabolic diseases	6	2,3%
Chronic myeloblastic leukemia	27	10,5%
Myelodysplastic syndromes	22	8,6%
Immunodeficiencies	22	8,6%
Organic cancers	5	1,9%
Total	257	100%

The aim of this paper is to assess the value of ultrasound in the diagnosis of hemorrhagic cystitis in pediatric patients undergoing hematopoietic stem cell transplantation as well as to determine the usefulness of ultrasonography in the assessment of the severity of changes and compare it with the Droller scale, laboratory test and cystoscopy results.

Material and methods

The study involved an analysis of the clinical material comprising disease data and medical test results of 334 patients who underwent hematopoietic stem cell transplantation at the Department of Bone Marrow Transplantation, Oncology and Hematology of the Medical University in Wrocław during the period from January 2008 to December 2012. The study group included 283 (84.5%) pediatric patients with cancer and 51 (15.5%) with non-neoplastic diseases, such as severe combined immunodeficiencies, congenital metabolic diseases and aplastic anemia. Taking into account the hematopoietic blood cell types, three kinds of transplants were listed: allogeneic – in 257 (76.5%) patients, autologous – in 78 (23.2%), and syngeneic – in 1 (0.3%).

The group of patients who underwent allogeneic transplantation consisted of 91 (35.4%) children under the age of 5, 57 (22.2%) children between 5 and 10, 109 (42.4%) children aged 10, and the entire group was predominated by boys (61.5%). In autologous transplant group 33 (43.3%) patients were below 5 years of age, 11 (14.1%) between 5 and 10, and 34 (43.6%) above 10, and the group was also predominated by boys – 52 (66.7% girls – 26). The characteristics of the group of children with allogeneic transplants and the types of initial diagnosis are presented in tab. 1.

The characteristics of the group of patients with autologous transplants and the initial diagnoses are presented in tab. 2. The table includes diagnoses in children who received autogenic transplants.

Tab. 2

Diagnoses in the group of pediatric patients with autotransplants

Diagnosis	Number of patients	Percentage of patients
Acute lymphoblastic leukemia	2	2,6%
Acute myeloblastic leukemia	11	14,1%
Lymphomas	9	11,5%
Organic cancers	56	71,8%
Total	78	100%

The first stage of the study involved an analysis of the incidence and nature of complications occurring after hematopoietic stem cell transplantations depending on patients’ gender and age, the type of primary disease, the source of progenitor cells, and the type of transplant. It also included an evaluation of diagnostic imaging results with particular emphasis on ultrasound. In the second stage an analysis of ultrasound images obtained in 42 patients diagnosed with hemorrhagic cystitis was carried out.

The incidence and types of complications following a transplantation of progenitor cells are presented in fig. 1.

Fig. 1

The most common complications following the transplantation

The ultrasound was performed with a BK Pro Focus apparatus with the use of the B-mode presentation and the Doppler techniques: color Doppler, power Doppler and duplex Doppler. The ultrasound images were recorded in the form of photographic documentation from a videoprinter and in the digital form on an ultrasound disc. The choice of the transducer heads for testing depended on patient's age and size. Infants and small children were tested with a 3.3–5.0 MHz frequency transducer head, older children and adults with a 2.5–6 MHz one. Additionally, all patients were tested with a 6–12 MHz linear transducer head.

The B-mode ultrasound test evaluated bladder capacity, the thickness of bladder walls and the presence of abnormal structures in its lumen, while the Doppler options tested the vascularity of the wall, as well as the nature and parameters of the vascular flow. According to Jequier and Rousseau, a normal wall of a full bladder in children has the thickness of 0.3 cm(. The assessment of the bladder wall thickness also included the evaluation of the length of the affected section of the wall. The sizes of clots were assessed according to the following criteria: small blood clots – up to 1 cm, medium ones – 1–3 cm, large ones – more than 3 cm. Next, the number of the clots (single or multiple) and their location (extending along the wall or located centrally) were determined. If the clots were connected, the size of the entire “conglomerate” was evaluated or it was analyzed how much of the volume of the bladder lumen it occupied. The results of the bladder ultrasound were compared with the Droller scale presented in tab. 3. In the course of the examination attention was also paid to other irregularities. Altogether, the results of 843 abdominal ultrasound tests were analyzed in all the patients.

Tab. 3

The Droller scale – the assessment of the severity of inflammation in the urinary bladder in pediatric patients after a bone marrow transplant (BM)

1. degree	microscopic hematuria
2. degree	macroscopic hematuria
3. degree	macroscopic hematuria with small clots
4. degree	severe macroscopic hematuria with massive clots causing tamponade and urinary obstruction, requiring instrumentation for clot evacuationto clear the urinary tract

A vast majority of the tests were performed during the period of up to 100 days after the infusion of hematopoietic cells (the so-called early post-transplant period).

The patients’ data used for the statistical analysis were stored in the STATISTICA computer database and the analyses were carried out using the STATISTICA 7.0 StatSoft package. The distribution type was checked for all measurable (quantitative) variables. The Shapiro–Wilk test and the χ2 (chi-squared) test were applied. The significance of differences in mean values in more than two groups (the results of clinical trials in subgroups with varying degrees of the severity of changes) were verified using the one-way analysis of variance (ANOVA).

Results

In the analyzed patient group hemorrhagic cystitis was found in 42 (12.5%) children who underwent allogeneic transplantation. Thirty one (73.8%) received a transplant from unrelated donors, 11 (26.2%) from compatible siblings, which required the most aggressive prophylaxis against graft-versus-host disease in the cases where the donor of the transplant material was unrelated.

The statistical analysis showed no significant correlation between patients’ gender, type of the underlying disease, the source of progenitor cells and the occurrence of hemorrhagic cystitis (p > 0.05). There was, however, a statistically significant correlation between the patients’ age and the incidence of the complication. It occurred significantly more often in children over the age of 10, as shown in tab. 4.

Tab. 4

A correlation between hemorrhagic cystitis and patients’ age and the chi-square test result

Hemorrhagic cystitis	Age group			Total
	Below 5	5–10	Over 10
Yes	10	5	27	42
No	113	63	116	292
Total	124	68	143	334
χ23 = 9,07; p = 0,0107.

In the analyzed group of 42 children the most commonly diagnosed hemorrhagic cystitis severity grade was grade 3 on the Droller scale – this result was confirmed in ultrasound tests carried out in all the patients. Grade 3 was found in 18 (42.9%) children, grade 2 – in 13 (30.9%), grade 4 – in 6 (14.3%) and grade 1 – in 5 patients (11.9%). The number of ultrasound tests depended on the severity of hemorrhagic cystitis, its duration and co-occurrence of other complications following the transplantation and it was within 1–15 range (median of 4.6 tests). Grades 3 and 4 of hemorrhagic cystitis were associated with the poor clinical condition of the patient, as well as their longer hospitalization. During this period there was an increased risk of serious complications, such as renal malfunction and failure, post-inflammatory narrowing of the ureters, hydronephrosis, and in grade 4 the fibrosis of the bladder with reduced bladder capacity(.

Forty one out of 42 children were diagnosed with the bladder wall thickening greater than 0.5 cm, 1.0 cm on average (fig. 2). In 14 patients it was sectional and in 22 the entire bladder wall was thickened (fig. 4, 5). The statistical analyses revealed a significant correlation between the inflamed, thickened bladder wall in the ultrasound image and the severity of hemorrhagic cystitis, as shown in tab. 5.

Fig. 2

Thickened bladder wall in a 6-year-old boy with juvenile myelomonocytic leukemia after hematopoietic cell transplant from the mother – grade 3 of hemorrhagic cystitis on the Droller scale

Fig. 3

Irregular thickening of the wall with hypervascularization and small blood clots in a 5-year-old girl with acute lymphoblastic leukemia after progenitor cell transplant from a compatible sibling

Fig. 4

Segmental bladder wall thickening with mucosal and sub-mucosal edema and hypervascularization

Tab. 5

A correlation between changes in the bladder wall (edema, loss of definition, increased diameter) in the ultrasound image and the clinical grade of hemorrhagic cystitis severity

Grade of hemorrhagic cystitis severity	Thickening of the wall		Number of patients
	Yes	No
1	4	1	5
2	13	0	13
3	18	0	18
4	6	0	6
Total	41	1	42
χ23 = 7,58; p = 0,056.

Four patients with grade 1 of hemorrhagic cystitis (80%) were diagnosed with segmental wall thickening, 8 with grade 2 (61.5%) with the thickening of the entire wall or a portion thereof. In 15 (83.3%) children with grade 3 of hemorrhagic cystitis changes were revealed in the entire bladder (fig. 3). In all patients with grade 4 the ultrasound image showed a significant degree of the thickening of the entire wall of the bladder – over 1.9 cm (figs. 4, 5). The results of these tests are shown in tabs. 6 and 7.

Fig. 5

Bladder wall thickened to 1.1 cm in the course of grade 2 hemorrhagic cystitis in a 5-year-old boy with acute lymphoblastic leukemia after progenitor cell transplant from a compatible sibling

Tab. 6

Types of changes in the bladder wall – “segmental” occupation or occupation of the entire bladder in various severity grades on the Droller scale

Grade of hemorrhagic cystitis severity	Thickening of the wall		Number of patients
	Segmental	Whole
1	4	0	4
2	8	1	9
3	2	15	17
4	0	6	6
Total	14	22	36

Tab. 7

The average thickness of the bladder wall in various grades of hemorrhagic cystitis

Grade of hemorrhagic cystitis severity	Average thickness of the wall [cm]
1	0,58
2	0,93
3	1,47
4	1,98

A study of vascular flows in the bladder wall showed a significant correlation between an increased number of vessels and the severity grade of hemorrhagic cystitis, which is presented in tabs. 8 and 9.

Tab. 8

A correlation between increased vascular flow through the bladder wall and hemorrhagic cystitis severity

Grade of hemorrhagic cystitis severity	Increased vascular flow through the wall		Number of patients
	Yes	No
1	2	3	5
2	7	6	13
3	15	3	18
4	6	0	6
Ogółem	30	12	42
χ23= 8,04;p= 0,045.

Tab. 9

The presence of clots in the bladder depending on the severity grade of hemorrhagic cystitis

Grade of hemorrhagic cystitis severity	Clots in the bladder		Number of patients
	Yes	No
1	1	4	5
2	8	5	13
3	16	2	18
4	6	0	6
Ogółem	30	12	42
χ23= 12,7; p = 0,005.

In grades 1 and 2 the hypervascularization of the wall was diagnosed in 9 out of 18 (50%) patients, while in grades 3 and 4 in 21 out of 24 (87.5%) cases.

The ultrasound examination showed a nearly 100-per cent sensitivity in the detection of blood clots in the bladder.

Their presence was significantly higher in more severe forms of hemorrhagic cystitis, which was confirmed by endoscopic tests of the bladder (figs. 6, 7).

Fig. 6

Severe bladder wall thickening of over 1.5 cm with edema and loss of definition of the structure of the surrounding tissues – grade 3 hemorrhagic cystitis in a 15-year-old boy with non-Hodgkin's lymphoma after allogeneic transplant from an unrelated donor

Fig. 7

Significant thickening of the wall with edema, inflammatory reaction around the bladder wall and the surrounding tissues, hypervascularyzation and clots in the bladder lumen

The clots were detected mainly in patients with hemorrhagic cystitis grade 3 and 4.

In the examined group of children the location of clots was not always compatible with the Droller scale. In 5 patients with grade 2 of hemorrhagic cystitis the clots were visualized in the lumen of the bladder, in 4 – extending along its walls. In 6 (37.5%) patients with grade 3 multiple clots were found in the lumen of the bladder, in another 6 (37.5%) – both in the lumen and extending along the walls, in 4 (25%) – only the latter.

In 6 children with grade 4 massive clots filling over 50% of the bladder volume were revealed, as shown in tab. 10.

Tab. 10

The size of clots in different severity grades of hemorrhagic cystitis

Grade of hemorrhagic cystitis severity	Size of clots [cm]			Total
	Up to 1	1–2	More than 2
1	0	0	0	0
2	5	2	0	7
3	3	11	2	16
4	2	0	2	4
Ogółem	10	13	4	27
χ24 = 12,2; p = 0,016.

In 35 patients endoscopic examinations confirmed the ultrasound diagnosis of the damage to urothelium and the inflammation of the bladder wall. In 7 children the complication after hemorrhagic cystitis was bilateral hydronephrosis caused by the obstruction of urinary outflow from the renal pelvis. The impediment to the outflow of urine and its stagnation in the collecting systems caused a renal malfunction manifested by increased levels of creatinine and urea in the serum. The B-mode imaging technique and the Doppler technique revealed a significant widening of the pelvicalyceal system and changes in the spectral Doppler of renal blood flow with an increase in vascular resistance and systemic vascular resistance index and with variations in laboratory tests. Impaired renal tissue structure was found in 17 of 42 patients with hemorrhagic cystitis (40.5%), which depended on the severity of the disease.

Discussion

Hemorrhagic cystitis is one of the most frequent complications following hematopoietic stem cell transplantations and as such it is an important clinical problem. Among the 334 analyzed patients 42 children were diagnosed with hemorrhagic cystitis (12.5%). All children in the study group who were diagnosed with hemorrhagic cystitis had undergone allogeneic transplantations. In the available literature, the incidence of this complication following allo- HSCT ranges from 6 to 26.9%%(.

The conducted statistical analyses revealed no significant correlations between patient's sex, type of the underlying disease, the source of progenitor cells, and the incidence of hemorrhagic cystitis, which is consistent with the findings made by other authors(.

A statistically significant risk factor of the hemorrhagic cystitis incidence was the patient's being over 10 years old, which also noted by other authors, although a different age limit was adopted(. In the studies by Gorczyńska( and Seber et al.( older children were more than 10 years old, in the study by Konda et al.( they were over 6.

Hemorrhagic cystitis is clinically manifested mostly by suprapubic pain, urinary frequency, hematuria and excretion of blood clots of various sizes. This clinical picture in children after hematopoietic stem cell transplantation is an indication for an ultrasound of the abdomen, kidneys and bladder. In the described patient group all the tests were analyzed by the authors after the onset of symptoms suggesting the beginning of hemorrhagic cystitis. The literature emphasizes the role of ultrasonography in the diagnosis of hemorrhagic cystitis(. This non-invasive test enables a morphological evaluation of the bladder wall, its thickness and structure, and allows to assess its vascularization. Moreover, it enables the evaluation of the bladder lumen, the presence of blood clots, their number, size and location, and also allows to assess the function of kidneys.

The symptoms of hemorrhagic cystitis are related to damaged urothelium and an inflammatory process within the walls of the bladder, which in ultrasound manifests itself as their thickening, loss of definition, change in the structure and hypervascularization. In the discussed patient group thickened bladder walls were observed in 97.6% children with clinically diagnosed hemorrhagic cystitis. In the statistical analysis no correlation between the occurrence of the bladder wall edema and a severity degree of hemorrhagic cystitis according to the Droller scale was observed. This is due to the fact that the urinary bladder wall thickening occurred in all patients with hemorrhagic cystitis. It must therefore be assumed that it was a characteristic feature of the complication in the studied group and it could serve as a basis for the diagnosis, but could not help determine the severity of changes. It was observed that there were differences in the location of the swelling, depending on the hemorrhagic cystitis severity. Segmental wall thickening occurred more frequently in lighter forms of hemorrhagic cystitis (grades 1 and 2), and the swelling and an increase in the diameter of the entire bladder wall affecting the tissues surrounding the bladder – in severe ones (grades 3 and 4). In various grades of the clinical advancement of hemorrhagic cystitis according to the Droller scale there was a significant change in the average bladder wall thickness measured in centimeters – of about 0.6 cm in grade 1 and 2 to about 2 cm in grade 3 and 4. It can be assumed that with each grade of severity the thickness of the bladder wall increases by about 0.5 cm.

Similar results concerning the morphological changes of the bladder wall were obtained in the studies by Cartoni et al. (, who analyzed the results of ultrasound tests in 12 patients with hemorrhagic cystitis and compared them with cystoscopy results. The endoscopy confirmed mucosal hyperemia, increase in telangiectasia, and enlarged area of active bleeding in the bladder in patients with severe forms of hemorrhagic cystitis. In her study McCarville emphasized the role of the Doppler ultrasound in the assessment of hemorrhagic cystitis severity in patients after bone marrow transplantation(.

In 71.4% of pediatric patients the ultrasound revealed bleeding into the lumen of the bladder with the formation of clots in various stages of evolution. A similar incidence of bleeding from the wall of the bladder and the formation of clots in its lumen was demonstrated by Cartoni et al. in their studies – 41.7% and 36%, respectively%(. This work, however, concerns a much smaller group of patients (12 and 11, respectively) and the percentage of patients with milder forms of hemorrhagic cystitis is also bigger.

The performed statistical analyses revealed a correlation between the occurrence of posthemorrhagic complications in which blood clots of various sizes were present in the bladder and the severity grade of hemorrhagic cystitis. Posthemorrhagic complications with the formation of clots taking up over 50% of the volume of the bladder were more common in grades 3 and 4. However, a correlation between the location of the clots and the severity of the complication was not observed, especially since in many cases the clots were visible both extending along the walls of the bladder as well as in its lumen.

In diseases involving tissue damage there is an increasing concentration of acute phase protein (CRP) which eliminates the generated toxic substances. Due to its high sensitivity and specificity, it is an important diagnostic parameter and the changes in the inflammatory process may be quickly referred to its concentration in the serum. Eighty-eight percent of pediatric patients with changes in the bladder wall detected in the ultrasound were diagnosed with a higher level of CRP, which demonstrated a significant correlation between the measured features (p < 0.05). In other available studies such a correlation was not investigated, which has undoubtedly confirmed the value of ultrasonography in the diagnosis of hemorrhagic cystitis.

Hemorrhagic cystitis may lead to retention of urine in the renal collecting systems. This complication was not frequent in the analyzed patient group. A statistical analysis of 7 cases showed a significant correlation between the incidence and severity of hydronephrosis and hemorrhagic cystitis. Out of 42 children diagnosed with hemorrhagic cystitis urine retention in the renal systems was observed in 7 patients (16.7%), and the complication concerned patients with severity grade 4 on the Droller scale. The most likely cause of hydronephrosis in these cases was the closure of the mouths of the ureters by conglomerates of clots. Hydronephrosis occurred in 5 patients with a lower degree of hemorrhagic cystitis severity, but the inflammatory process was prolonged in these cases. The chronic inflammation resulted in impairing bladder contractility. Limited systolic and diastolic functions of the bladder led to a reduction of its capacity, vesicourethral reflux and urinary stagnation. In 8 children a prolonged impeded outflow of urine from the kidneys caused by hemorrhagic cystitis resulted in impaired renal function manifested as abnormalities in laboratory tests (creatinine concentrations in the serum and GFR – glomerular filtration rate). Nephrotoxic agents, treatment with the use of kidney-damaging drugs and/or drugs with a narrow therapeutic range excreted mainly through the kidneys, nephrotoxic viruses including BKV, hypovolemic shock or septic shock resulted in the damage to renal parenchyma in 10 patients, which in the ultrasound imaging was manifested as the loss of definition of the echostructure of renal parenchyma and changes in the Doppler spectrum of renal flow. Drugs that most commonly cause hemorrhagic cystitis include cyclophosphamide and busulfan. Both are used in high-dose chemotherapy prior to hematopoietic stem cell transplantation(. They belong to chemotherapeutic agents from the group of alkylating drugs used in the treatment of neoplastic diseases. Active metabolites of the drug, 4-hydroxycyclophosphamide and aldophosphamide are transported through the bloodstream to tumor cells. Aldophosphamide undergoes spontaneous fission into phosphoramide and acrolein, which are excreted in the urine(.

Acrolein has toxic effect on transitional epithelium that lines the urinary tract and can cause damage to the renal pelvis, ureters, bladder and urethra(.

Since urine, along with the toxic substances it contains, remains in the bladder the longest, it is there where the greatest damage is done. The degree of irritation of the transitional epithelium depends on the time of its contact with toxic compounds, as well as on their concentration in the urine. The longer and higher the concentration of irritants, the more massive damage is done to the bladder wall(. The main metabolite of busulfan in the urine is methane sulfonic acid, which in 10–50% is excreted through kidneys unchanged. This drug induces hyperplasia of the bladder epithelium, resulting in its damage(.

Some transplantation preparatory procedures involve total body irradiation (TBI), which does not remain indifferent to the individual organs. Hence, we cannot exclude the role of ionizing radiation in the physicochemical damage of the urothelium and in the etiology of the inflammatory process(. According to some authors, the role of TBI in the physical damage to the urothelium is small, but significantly compromises the immune system of the irradiated organism which becomes more susceptible to reactivation or de novo infection with cytopathic viruses(. Viruses that play the biggest role in the etiology of hemorrhagic cystitis include polyoma BK and JC human viruses. They belong to a family of viruses known as Papovaviridae group(. Much more rarely, patients with hemorrhagic cystitis are diagnosed with other viruses, such as JCV, ADV or SV-40(.

The BK virus is a non-enveloped virus with an icosahedral capsid and a genome containing circular DNA. It is widespread in nature. Primary infection with BKV occurs mostly in childhood by droplet transmission, rarely via the faecal-oral route. In 50% of 3–4-year-old children specific antibodies against BKV are found, while in adults this percentage is as high as 80%(.

Primary BKV infections occur frequently accompanied by symptoms of mild upper respiratory tract infections or show no symptoms at all. The viruses multiply in the epithelium of the respiratory tract, then enter the urinary system through the bloodstream. In patients with immunosuppression (including those after blood stem cells transplants) virus activation, viremia and viruria may occur. In immunocompromised patients the disease progresses, which is associated with viral replication in the nuclei of infected cells. BKV proliferation induces a cytopathic effect and cell lysis(. BKV reinfection may be asymptomatic or may manifest the signs of cell damage and strong inflammation of the bladder mucosa, resulting in the symptoms of hemorrhagic cystitis(.

The inflammatory response of the bladder wall and the clinical symptoms of the disease depend on the degree of patient's immunosuppression and the intensity of viral replication. The deeper the immunosuppression and the larger the viral load found in patient's urine, the more severe the clinical course of cystitis. The change of latent viruses into their active forms does not always cause clinical signs of hemorrhagic cystitis. They are observed only in less than 50% of patients after transplantation with confirmed viruria(. In many of these cases kidney damage occurs, which was confirmed in 17 patients. The diagnosis was based on the results of kidney ultrasound. Structural changes in the renal parenchyma were confirmed by laboratory tests in all the cases. Changes in the kidney ultrasound image were significantly more frequent in children with more severe forms of hemorrhagic cystitis, but it was not revealed in the first examination but usually in consecutive ones. A significantly more frequent renal function impairment with visible abnormalities in the ultrasound in children with grade 3 and 4 on the Droller scale may result from a massive infection with polyoma BK viruses which affect the urothelium that is already damaged due to conditioning.